Yan Wei, Shi Xue, Zhao Yun, Liu Xiaoyu, Jia Xueming, Gao Le, Yuan Jiahe, Liao Aijun, Yasui Hiroshi, Wang Xiaobin, Wang Xiaotian, Zhang Rui, Wang Huihan
Department of Hematology, Shengjing Hospital, China Medical University, Shenyang, China.
Department of Radiology, Shengjing Hospital, China Medical University, Shenyang, China.
Nat Commun. 2025 Mar 24;16(1):2863. doi: 10.1038/s41467-025-57966-5.
Gut microbiome influences tumorigenesis and tumor progression through regulating the tumor microenvironment (TME) and modifying blood metabolites. However, the mechanisms by which gut microbiome and blood metabolites regulate the TME in multiple myeloma (MM) remain unclear. By employing16S rRNA gene sequencing coupled with metagenomics and ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry, we find that Lachnospiraceae are high and phosphatidylcholine (PC) are low in MM patients. We further show that Lachnospiraceae inhibits PC production from MM cells and enhances cytotoxic CD8 T cell function. Mechanistically, PC promotes Sb9 mRNA maturation in MM cells by LIN28A/B via lysophosphatidic acid, thus enhances exosamal Sb9 production. Exosamal Sb9 then reduces GZMB expression by suppressing tumor protein p53 (TP53) UFMylation via the competitive binding of TP53 with the ubiquitin-fold modifier conjugating enzyme 1 in CD8 T cells. We thus show that Lachnospiraceae and PC may be potential therapeutic targets for MM treatment.
肠道微生物群通过调节肿瘤微环境（TME）和改变血液代谢物来影响肿瘤发生和肿瘤进展。然而，肠道微生物群和血液代谢物在多发性骨髓瘤（MM）中调节TME的机制仍不清楚。通过采用16S rRNA基因测序结合宏基因组学以及超高效液相色谱结合四极杆飞行时间质谱，我们发现MM患者中毛螺菌科丰度高而磷脂酰胆碱（PC）水平低。我们进一步表明，毛螺菌科抑制MM细胞中PC的产生并增强细胞毒性CD8 T细胞功能。机制上，PC通过LIN28A/B经由溶血磷脂酸促进MM细胞中Sb9 mRNA成熟，从而增强外泌体Sb9的产生。然后，外泌体Sb9通过在CD8 T细胞中TP53与泛素折叠修饰结合酶1的竞争性结合抑制肿瘤蛋白p53（TP53）的UFMylation，从而降低GZMB表达。因此，我们表明毛螺菌科和PC可能是MM治疗的潜在靶点。
